Glucose Homeostasis

By Dr. Sumbul Fatma

Glucose homeostasis
A process that
Controls glucose metabolism and Maintains blood glucose level in the body

Glucose is a major source of bodys energy The liver plays a key role in maintaining blood glucose level Blood glucose level is tightly controlled because the brain constantly needs glucose Severe hypoglycemia can cause coma and death Chronic hyperglycemia results in glycation of proteins, endothelial dysfunction and diabetes

Sources of glucose
Dietary sources: Dietary CHO is digested in the GI to monosaccharides Starch provides glucose directly Fructose and galactose are converted to glucose in the liver Metabolic sources (via gluconeogenesis): Glycerol, lactate, pyruvate, glucogenic amino acids

Phases of glucose homeostasis

Five phases:
Phase I (Well-fed state) Phase II (Glycogenolysis)

Phase III (Gluconeogenesis)

Phase IV (Glucose, ketone bodies (KB)

oxidation) Phase V (Fatty acid (FA), KB oxidation)

Phase I (Well-fed state)

Glucose is mainly supplied by dietary CHOs

Liver removes about 70% of glucose load after a

CHO meal All body tissues use dietary glucose for energy in this phase Some glucose is converted to glycogen for storage in the liver (glycogenesis)

Phase I (Well-fed state) contd..

Excess glucose is converted to fatty acids and

triglycerides in the liver These are transported via VLDL (very low density lipoproteins) to adipose tissue for storage Gluconeogenesis is inhibited in this phase Cori and glucose-alanine cycles are inhibited

Phase II (Glycogenolysis)
Phase II starts during early fasting when dietary

glucose supply is exhausted Hepatic glycogenolysis maintains blood glucose level in this phase Glycogenolysis is the major source of blood glucose in this phase

Phase III (Gluconeogenesis)

Phase III starts when glycogen stores in liver are

exhausted (within 20 hours) Duration of phase III depends on

Feeding status Hepatic glycogen stores Physical activity

Hepatic gluconeogenesis from lactate, pyruvate, glycerol and alanine maintains blood glucose level Gluconeogenesis is the major source of blood glucose in this phase

Phase IV (Glucose and KB oxidation)

Several days of fasting leads to phase IV
Gluconeogenesis starts to decrease KB accumulation increases which enter the brain

for energy production Brain uses both glucose and KB for energy

Phase V (FA and KB oxidation)

Prolonged fasting leads to phase V Less dependence on gluconeogenesis All body tissues use FA and KB oxidation for

energy production Gluconeogenesis somewhat maintains blood glucose level in this phase

Phase V (FA and KB oxidation

High KB conc. and glucose levels inhibit

proteolysis in muscle (conservation of muscle) When all fat and KBs are used up Body uses muscle protein to maintain blood glucose level

Hormones and glucose homeostasis

Hormones that regulate glucose metabolism: Insulin (lowers blood glucose level) Glucagon Somatostatin Cortisol Antagonize insulin action Growth hormone Adrenaline

Insulin
Plays a major role in glucose homeostasis Synthesized by the b-cells of islets of Langerhans of pancreas A small protein composed of two chains Formed as prepro-insulin and converted to pro-insulin upon secretion Rise in blood glucose level stimulates insulin secretion Promotes entry of glucose into cells

Insulin actions

Mechanism of action
The insulin receptor is present on the plasma membrane of cell Composed of
2a-subunit (extracellular)

2b-subunit (cytoplasmic)

Binding of insulin to a-subunit causes phosphorylation of b-subunit This activates the receptor The activated receptor then phosphorylates intracellular proteins generating a biological response

Insulin and CHO metabolism

Promotes glucose uptake into cell: Glucose is diffused into cells through hexose transporters such as GLUT4 GLUT4 is present in cytoplasmic vesicles Insulin binding to its receptor causes vesicles to diffuse into plasma membrane GLUT4 is inserted into the membrane Allowing glucose transport into the cell Brain and liver have non-insulin dependent glucose transporter

Insulin and CHO metabolism

Stimulates glycogen synthesis Decreases blood glucose levels Increases glycolysis Stimulates protein synthesis Insulin deficiency causes diabetes mellitus Hyperinsulinemia is due to insulin resistance in:
Diabetes mellitus or Metabolic syndrome

Glucagon
A peptide hormone secreted by a-cells of pancreatic islets Secreted in response to hypoglycemia Increases glucose levels Stimulates glycogenolysis Activates hepatic gluconeogenesis

Somatostatin
A peptide hormone secreted by -cells of

pancreatic islets, stomach and intestine An inhibitory hormone Inhibits secretion of both insulin and glucagon Affects glucose homeostasis indirectly

Glucocorticoids (Cortisol)
Cortisol is a steroid hormone secreted by adrenal

gland Contributes to glucose homeostasis Maintains normal glucose levels in fasting Stimulates gluconeogenesis in the liver Mobilizes amino acids for gluconeogenesis Inhibits glucose uptake by cells Stimulates fat breakdown in adipose tissue

Growth hormone
A protein hormone secreted by anterior pituitary

gland Maintains blood glucose levels by: Inhibiting insulin action Stimulating gluconeogenesis in the liver

Epinephrine
A catecholamine hormone secreted by adrenal

gland Stimulates lipolysis in adipose tissue when glucose blood levels fall Promotes glycogenolysis in skeletal muscle

References
Textbook of biochemistry with clinical correlation by

Devlin Lippincott